More than 60 million people have been infected with the human immunodeficiency virus (“HIV”), the causative agent of acquired immune deficiency syndrome (“AIDS”), since the early 1980s. See Lucas, 2002, Lepr Rev. 73(1):64-71. HIV/AIDS is now the leading cause of death in sub-Saharan Africa, and is the fourth biggest killer worldwide. At the end of 2001, an estimated 40 million people were living with HIV globally. See Norris, 2002, Radiol Technol. 73 (4):339-363.
Modern anti-HIV drugs target different stages of the HIV life cycle and a variety of enzymes essential for HIV's replication and/or survival. Amongst the drugs that have so far been approved for AIDS therapy are nucleoside reverse transcriptase inhibitors (“NRTIs”) such as AZT, ddI, ddC, d4T, 3TC, and abacavir; nucleotide reverse transcriptase inhibitors such as tenofovir; non-nucleoside reverse transcriptase inhibitors (“NNRTIs”) such as nevirapine, efavirenz, and delavirdine; protease inhibitors (“PIs”) such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir and atazanavir; and fusion inhibitors, such as enfuvirtide.
Nonetheless, in the vast majority of subjects none of these antiviral drugs, either alone or in combination, proves effective either to prevent eventual progression of chronic HIV infection to AIDS or to treat acute AIDS. This phenomenon is due, in part, to the high mutation rate of HIV and the rapid emergence of mutant HIV strains that are resistant to antiviral therapeutics upon administration of such drugs to infected individuals.
Many such mutant strains have been characterized in order to correlate presence of the mutations in the strains with resistant or susceptible phenotypes. For example, the M184V mutation in reverse transcriptase is known to correlate with resistance to a number of NRTIs, including, for example, abacavir and lamivudine. See, e.g., Durant et al., 1998, Lancet 353:2195-9. In addition, the M184V mutation is also known to correlate with hypersusceptibility to efavirenz. See Shulman et al., 2001, AIDS 15:1125-1132. Thus, a given mutation may correlate with resistance to one or more antiviral agent and hypersusceptibility to one or more others.
Further, hypersusceptibility to NNRTIs such as efavirenz and/or nevirapine has been shown to be clinically relevant to treatment of patients infected with HIV-1 hypersusceptible to treatment with such agents. See, for example, Haubrich et al., 2002, AIDS 16:33-40; Shulman et al., 2001, AIDS 15:1125-1132; Bosch et al., 2003, AIDS 17:2395-2396; and Hammer et al., 2002, J.A.M.A. 288:169-80.
Though numerous mutations associated with both resistance and susceptibility to particular anti-viral agents have been identified, the effects of these mutations on resistance or susceptibility to other antiviral agents in many cases remains obscure. Thus, an analysis that identifies the effects of mutations associated with resistance to one antiviral agent on resistance or susceptibility to other antiviral agents would be very useful in guiding selection of particular antiviral agents in guiding therapeutic decisions in the treatment of HIV-infected individuals. Further, in view of the clinical relevance of NNRTI hypersusceptibility, a more complete understanding of mutations associated with such hypersusceptibility is also needed. For the first time, these, as well as other unmet needs, will be achievable as a result of the invention described hereinafter.